Preparation of 2-amino-4-hydroxy-6-methyl pteridine



Patented July 26, 1949 BREBARA'IIIQN. OF ZE-AMINO A-HYDROXY-G- METHYL PTERIDINE corporaitiom olil Maine No- Drawing; Application; June 4,. I948, SerialNo. 31,217

e claims. (01. 26.0-25.1)-

This invention relates to an improved method of. preparing 2 -amino -4 -hydroxy'- 6--methyl pteridine. This compound can alsobe named 2 amino 45 hydroxy 6 methylpyrimido-- E4,5'-b lpyrazine.

Inthefl'o-pending application of John-H. Mowat, Serial No. 633,870; filed December 8, 1945, now Patent No. 2,443,078, adescription" of 2-amino- 4.-hydroxy B-methylpyrimidoE4,5-blpyrazine and its preparation is given. This compoundis prepared by reacting 23,4;5-triamino-6hydroxypyrimidine with" methyhgammaggammai-dimethoxy acetoacetate to obtain an intermediate product which isdecarboxylated-tb give thecompound desired. Other methods have been developed for the preparation of this compound such as by the reaction of 2*,4',5-tri'amino-6- hydroxypyrimidine with methyl glyoxal". However, in these methods a secondprod'uct; 2-'-amino- 4-hydroxy-7-methyl pteridine, is also obtained to some extent. Only the Z-aminoA-hydroxy- G-m'ethyl' pteridine can be used as anintermediate to obtain folic acid. The 2-a'mino'-4.-hyd'roxy- 'l-rnethyl pteridine is therefore, an undesirable side. reaction product, the formation of which tends to lower the yield of the desired 2-amino- 4-hydroxy-6-methyl pteridine,

I have found that 2-amino-l-hydroxy-fi-methyl pterdine can be produced in excellent yields by reacting 2,4,5-triamino-G-hydroxypyrimidine or a salt thereof with methyl glyoxal in the presence of the S03- ion at a pH less than 8.5. The product obtained under these conditions is almost entirely the fi-substituted isomer. The S0;- ion is most easily supplied by the addition of an alkali metal, alkaline earth metal or ammonium sulfite or bisulfite to the reaction mixture.

The intermediates 2,4,5-triamino-6-hydroxypyrimidine and methyl glyoxal are known compounds and may be prepared by methods which have been described in the chemical literature. In addition to methyl glyoxal, acetals thereof may be used in the process such as methyl glyoxal dimethyl acetal, methyl glyoxal diethyl acetal, methyl glyoxal dipropyl acetal, methyl glyoxal diisopropyl acetal, methyl glyoxal dibutyl acetal and the like. However, I believe that in any event the reaction which takes place is between methyl glyoxal and the triamine.

2. water miscible solvents such as lower aliphatic alcohols, dioxane, and. the like can also be used. As stated above the intermediate prepared in the present? inventionis. useful in the preparation of; pteroylglutamic acidand peptides thereof. To

prepare these compounds the intermediate is.

first halogenated and thenreacted. with paraaminobenzoylglutamic' acid, or a peptide thereon A number of experiments were carried out. in.

which 2,4,5-tri'amino-fi-hydroxypyrimidine. was. reacted with methyl glyoxal at a pH varying.

from 3 to 9 and in the presence or absence. of

the S03 ion. When 2.14 g. of 2.4-,5-trian1inofi hydr'oxypyrimidine is reacted with 2.6 g. of

30% methyl glyoxal in 200 cc of water atapH of 3 in the presence of the S03? ion a productv isobtained; which is predominately 2-amino-4i-- hydroxy-(i-methyl pteridine as shown by spectregraphic analysis. Another experiment carried out at a. pH of5 under the same conditions,gave. However, it was found that. if

similar results. the 803- ion was not present under these conditions thev product obtained was. predominately the 'T-met'hyli isomer. Other experimentscarried out at a pH of 7,. 8 and 8.5 in the, presence of The reaction may be carried out at temperatures within the range of from about 0. C. up to about 100 C.

In carrying out the reaction a substantially aqueous solvent is used. Mixtures of water and the S03- ionshowedthe product obtained. was 2 -ami'no bbydroxy-Gmethyl pteridine. Never theless, under these same conditions in the absence of the 803' ion most of the product was the l-methyl isomer. Other experiments were conducted under the conditions given above at a pH of 9 both in the presence and the absence of the S03 ion. It was found that under either conditions the product obtained was predominately 2-amino-4-hydroxy-7-methyl pteridine.

In accordance with the group of experiments carried out above in order to obtain predominately 2-amino-4-hydroxy-6-methyl pteridine from the reaction of 2,4,5 triamino 6 hydroxypyrimidine and methyl glyoxal the pH is less than 8.5 and the 803- ion is present.

The following examples illustrate the method of the present invention in greater detail.

Example 1 A solution of 30 g. of sodium sulfite in ml. of water is prepared and the pH adjusted to 7. To this is added a solution of 2.14 g. of 2 4,5- triamino-6-hydroxypyrimidine dihydrochloride in a small amount of water. The mixture is heated on a steam bath to about 98 C. and over a period of 5 minutes 2.35 ml. of 30.7% methyl glyoxal dissolved in 7 ml. of water containing 1 g. of sodium bisulfite is added. The mixture is cooled to room temperature, filtered and the precipitate 3 washed with water and ethanol. A yield'oi 1.5 g. of product is obtained which on spectroscopic analysis is predominately 2-amino-e-hydroxy-6- methylpyrimido [4,5 -b pyrazine.

Example 2 A solution of 30 g. of sodium sulfite in 90 ml.,

of water is prepared and the pH adjusted to 7. To this is added 2.14 g. of 2,4,5-tri-amino-6- The precipitate is Washed with Warm water and dried. A yield of 1 g. of 2-amino-4-hydroxy- 6-methylpyrimido[4,5-lo]pyrazine is obtained.

Example 3 A solution of 600 g. of sodium sulfite in 1800 cc. of water is warmed slightly and the pH adjusted to 7 with concentrated hydrochloric acid. To this is added 42.8 g. of 2,4,5-tr1'amino-6-hydroxypyrimidine dihydrochloride dissolved in a minimum amount of water and the pH again adjusted to 7. The mixture is warmed, to 45 to 47 C. to get most of the material into solution. To this solution over a period of 10 minutes is added 47 cc. of 30.7% methyl glyoxal diluted to 100 cc. and containing 10 g. of sodium 'bisulfite. The mixture is stirred for one-half hour, the product filtered off and recrystallized from 2 N. sodium hydroxide. A yield of 27 g. of 2-amino-4 hydroxy-fi-methylpyrimido[4,5-blpyrazine is obtained.

A solution of 200 mg. of the product obtained above in ml. of Water is prepared. To this is added 10 m1. of 2 N. potassium permanganate. The mixture is heated on a steam bath for three hours, following which 1 ml. more of potassium permanganate solution is added and the heating continued for 3 hours more. The maganese dioxide is filtered off and the filtrate made acid with acetic acid. The product obtained is 2- amino 4 hydroxypyrimido [4,5 blpyrazine-G- carboxylic acid, yield 144 mg.

The above experiment shows that the original process gives the desired G-methyl pteridine since on oxidation the corresponding G-carboxylic acid pteridine is obtained. a

I claim:

1. A method of preparing 2-amino-4-hydroxy- G-methylpyrimido [4,5-blpyrazine which comprises reacting 2,4,5-triamino-G-hydroxypyrimidine with methyl glyoxal in a substantially aqueous solvent in the presence of the 803* ion and at a pH less than 8.5.

2. Amethod of preparing 2-amino-4-hydroxy- 6-methylpyrimido [4,5-blpyrazine which comprises reacting 2,4,5-triamino-6-hydroxypyrimidine with methyl glyoXal in the presence of a. substantially aqueous solvent and a member of the group consisting of alkali metal and alkaline earth metal sulfites and bisulfites at a pH less than 8.5.

3.. A method of preparing 2-amino-4-hydroxy- S-methylpyrimido [4,5-blpyrazine which comprises reacting 2,4,5-triamino-G-hydroxypyrimidine with methyl glyoxal in the presence of a substantially aqueous solvent and'an alkali metal sulfite at a pH not greater than 8.5.

4. A method of preparing 2-amino-4-hydroxy- 6-methylpyrimido [4,5-blpyrazine which comprises reacting 2,4,5-triaminc-6-hydroxypyrimie dine with methyl glyoxal in the presence of a substantially aqueous solvent and sodium sulfite at a pH less than 8.5.

5. A method of preparing 2-amino-4-hydroxyfi-methylpyrimido [4,5-blpyrazine which comprises reacting 2,4,5-triamino-B-hydroxypyrimidine with methyl glyoxal in the presence of a substantially aqueous solvent and potassium sulfite at a pH less than 8.5.

6. A method of preparing 2-amino-4-hydroxyfi-methylpyrimido [4,5-blpyrazine which comprises reacting 2,4,5-triamino-(i-hydroxypyrimidine with methyl glyoxal in the presence of a substantially aqueous solvent and ammonium sulfite at a pH less than 8.5.

JOSEPH SEMB.

N 0 references cited. 

